Australian oncologists question calls for universal Next-Generation Sequencing in advanced cancer

21 Jun 2021

Australian oncologists have expressed doubts about a recommendation from US counterparts that next generation sequence (NGS) testing become a component of standard care for all patients with advanced cancer.

In an article in JAMA Oncology they have questioned the data behind the ‘expansive’ recommendation, arguing that study findings on which they are based are ‘far from a home run’ when it comes to supporting routine use of the costly tests.

The study, which first received prominence  when published in February, reports on the molecular profiling efforts undertaken in a single centre where NGS testing was performed on fresh tumour and blood samples from more than 1000 patients between 2011 and 2018.

The detailed molecular profiling included whole-exome or targeted-exome capture with analysis of 1700 genes and tumour transcriptome (RNA) sequencing.

Somatic and germline genomic mutations were then detailed and classified according to clinical therapeutic relevance, with the results returned to the treating oncologists

The US team, led by Dr Eric Cobain from the Department of Internal Medicine at the University of Michigan, found potentially clinically actionable genomic alterations in 817 patients.

Of these, 132 patients received sequencing-directed therapy (SDT), and 49 had clinical benefit. Exceptional responses were observed in 26 patients who remained on SDT for 12 months or longer.

The team identified 169 pathogenic germline variants  (PGVs) from 160 patients with 49 of these deemed as having potential tier 1 therapeutic implications.

For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), while SDT in 13 patients resulted in clinical benefit in seven instances (53.8%), including five exceptional responses.

The group’s findings prompted their recommendation that directed germline testing be standard of care in all patients with advanced cancer.

The ‘high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supported the use of comprehensive NGS profiling as a component of standard of care for those disease entities’, they added.

Thrilling possibilities

But in a letter to JAMA Oncology, Dr Catherine Dunn, Dr Lucy Gately and Professor Peter Gibbs from the Personalised Medicine Division of the Walter and Eliza Hall Research Institute (WEHI) in Melbourne, said while the study does demonstrate the ‘thrilling therapeutic possibilities’ associated with NGS testing, its universal use is not ready for ‘prime time’. 

Raising a number of concerns about the cost of broad NGS testing, the Victorian oncologists pointed out that only a small proportion of patients involved in the study went on to receive a targeted agent on the basis of NGS results. Furthermore, an even smaller proportion derived clinical benefit from sequencing-directed therapy (SDT).

“That 817 of 1138 patients enrolled (71.8%) had a potentially targetable mutation is intriguing, but this is far from a home run. Only 132 (11.6%) of the total cohort ever received a targeted agent. Moreover, 83 of 132 (62.9%) treated with sequencing-directed therapy received no clinical benefit,” they wrote.

The team also pointed out that randomised trials comparing clinical outcomes for patients receiving molecularly targeted therapy versus conventional therapy have failed to demonstrate a benefit of this approach.

With health care dollars already stretched, the reality of large-scale precision oncology approaches remained out of reach, according to Dr Dunn and colleagues. In their article they flagged alternative approaches such as simple immunohistochemistry and a focus on channelling integrated genomic profiling efforts on specific patient populations

It’s an approach which they said could potentially deliver ‘substantial benefit at a small fraction’ of the cost of universal NGS.

“The most frequently identified marker for exceptional benefit, homologous recombination repair defects, can be identified using limited panels. We suggest that the approach to personalised oncology must itself be personalised. Consideration must be given to factors such as the tumour subtype, which dramatically alters the yield of molecular testing.”

The oncologists added that the benefit of reflex molecular testing will be limited for tumours where standard of care treatment already exists, including targeted therapy, which are often prohibitively expensive outside of clinical trials, they point out.

“As always, prospective randomised clinical trials demonstrating clear patient and health system value should guide routine clinical practice,” they cautioned.

The study and comment are published in JAMA Oncology.

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